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Cellular cholesterol trafficking and compartmentalization

Key Points

  • The physiological functions of cholesterol occur in cells, rather than in plasma where it can easily be measured. Therefore, plasma cholesterol levels reflect the exchange of cholesterol between different cell types and tissues. In cells, cholesterol functions as an essential structural membrane component, and the metabolites of cholesterol have important biological roles as signal transducers and solubilizers of other lipids.

  • There is a limited molecular understanding of the pathways and metabolic processes that are associated with cholesterol. Experimental approaches need to be improved to detect the short-range spatial and temporal order that lipids generate within membranes. This is important to validate the postulated models of cholesterol-dependent lateral membrane organization in cellular membranes.

  • Cholesterol and sterol metabolizing enzymes (which produce biologically active products) are distributed heterogeneously between intracellular membranes and different cell types. Sterol delivery between these sites is an important means of regulating these enzyme reactions, and thus cholesterol activity.

  • Lipid transfer proteins can facilitate the inter-membrane transport of cholesterol, possibly through membrane contact sites. START and ORP family proteins function as sterol transporters or sensors that indirectly take part in sterol trafficking.

  • Lipoprotein cholesterol is delivered to acidic hydrolytic organelles by membrane transport. This process is also important for the release of cholesterol to physiological extracellular acceptors and for lipoprotein cholesterol secretion. In many cell types, several ABC transporters cooperate to release cholesterol to physiological extracellular acceptors, thereby facilitating cholesterol excretion from the body.

  • Finally, cellular cholesterol compartmentalization largely dictates the exchange of cholesterol between tissues and determines cholesterol physiology and pathology at the whole body level.

Abstract

Cholesterol is an essential structural component in the cell membranes of most vertebrates. The biophysical properties of cholesterol and the enzymology of cholesterol metabolism provide the basis for how cells handle cholesterol and exchange it with one another. A tightly controlled — but only partially characterized — network of cellular signalling and lipid transfer systems orchestrates the functional compartmentalization of this lipid within and between organellar membranes. This largely dictates the exchange of cholesterol between tissues at the whole body level. Increased understanding of these processes and their integration at the organ systems level provides fundamental insights into the physiology of cholesterol trafficking.

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Figure 1: Cholesterol metabolism.
Figure 2: Sterol regulatory element binding protein (SREBP) regulation of cholesterol metabolism.
Figure 3: Basic mechanisms of cholesterol transport between membranes.
Figure 4: Endosomal cholesterol trafficking.
Figure 5: Cholesterol efflux and reverse cholesterol transport.
Figure 6: Cholesterol trafficking in enterocytes.
Figure 7: Cholesterol trafficking in hepatocytes.

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Glossary

Familial hypercholesterolaemia

The most common monogenic defect of cellular cholesterol processing, with the majority caused by low density lipoprotein (LDL) receptor mutations. It results in high circulating LDL–cholesterol levels and premature atherosclerosis.

Lysosomal cholesterol–sphingolipid storage diseases

Monogenic diseases that are characterized by the accumulation of cholesterol and distinct sphingolipid species in late endocytic compartments, typically caused by defective degradation or endolysosomal export of the accumulating lipid(s), which manifest as neurodegenerative and visceral (liver, spleen) symptoms.

Enterocyte

The absorptive cell type in the intestine.

HDL

An 8–11-nm high density (1.063–1.210 g ml−1) lipoprotein with 55% protein (with APOA-I as the major apoprotein), 25% phospholipids, 15% cholesterol and 5% triglycerides.

Lipoprotein

A spherical particle that is used for the transfer of lipids and lipophilic substances in the circulation. It is composed of various amounts of phospholipids, cholesterol and triglycerides as well as apoproteins.

Statin

An inhibitor of hydroxymethylglutaryl CoA reductase (HMG-CoAR), the rate-limiting enzyme of cholesterol synthesis.

Sterol regulatory element binding protein

A membrane-tethered transcription factor that controls certain genes that are required for lipid synthesis and uptake.

COPII vesicle

A coated vesicle that is involved in transport from the endoplasmic reticulum to the Golgi.

Caveolae

Flask-shaped invaginations of the plasma membrane with a diameter of 60–80 nm. Caveolae are formed by the polymerization of caveolins and contain cholesterol and sphingolipids.

Flip-flop

Transmembrane translocation of lipids.

Oxysterol

A family of oxidized derivatives of cholesterol, which may arise from either enzymatic or non-enzymatic oxidation reactions.

Chylomicron

A 50–200-nm diameter, lowest density (<1.006 g ml−1) lipoprotein that is composed of 85% triglycerides, 9% phospholipids, 4% cholesterol, and 2% protein (with APOB48 as the major apoprotein).

VLDL

A 30–70-nm very low density (0.95–1.006 g ml−1) lipoprotein, with 50% triglycerides, 20% cholesterol, 20% phospholipids and 10% protein (with APOB100 as the major apoprotein).

LDL

A 20–25-nm low density (1.006–1.063 g ml−1) lipoprotein with 45% cholesterol, 20% phospholipids, 10% triglycerides and 25% protein (with APOB as the major apoprotein).

Reverse cholesterol transport

The process by which cholesterol is transported by HDL from extrahepatic tissues to the liver for excretion into bile.

ABC transporter

One of a family of membrane transport proteins that use the energy of ATP hydrolysis to transport various molecules, including cholesterol and other lipids, across the membrane.

Clathrin-coated vesicle

A transport vesicle that buds with the aid of a coat protein known as clathrin.

Multivesicular endosome

An intermediate organelle in endosome–lysosome transport that is characterized by small membrane vesicles enclosed within a limiting membrane. The internal vesicles are thought to form by invagination and budding from the limiting membrane.

Rab

A family of Ras-like small G proteins that control membrane trafficking. Rab proteins are modified by geranylgeranyl groups that anchor them to membranes and can be specifically localized to different compartments.

Atherosclerotic lesion

Deposition of cholesterol in the arterial wall, resulting in the invasion of monocyte–macrophages that scavenge the lipids and transform into foam cells. In advanced lesions, many cell types are affected and the lesion becomes prone to rupture, which may clog the artery.

Discoidal HDL

A precursor for a mature, spherical high density lipoprotein (HDL) particle that migrates with pre-β mobility in crossed immunoelectrophoresis (therefore, it is also called pre-β-HDL). It contains APOA-I, phospholipid and small amounts of cholesterol.

Stanol

A family of hydrated plant sterols.

Canalicular membrane

The apical plasma membrane of the hepatocyte that faces the bile canaliculus.

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Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nat Rev Mol Cell Biol 9, 125–138 (2008). https://doi.org/10.1038/nrm2336

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